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Tosylates in palladium-catalysed coupling reactions. Application to the synthesis of arylcoumarin inhibitors of gyrase B
TETRAHEDRON LETTERS Pergamon
Tetrahedron Letters 41 (2000) 1543–1547
Tosylates in palladium-catalysed coupling reactions. Application to the synthesis of arylcoumarin inhibitors of gyrase B Laurent Schio,∗ Fabienne Chatreaux and Michel Klich Medicinal Chemistry, Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France Received 16 November 1999; accepted 12 December 1999
Abstract The palladium-catalysed coupling reaction between tosylate derivatives and organostannanes has been investigated as a methodology for carbon–carbon bond formation. Aryl substituents have been successfully incorporated even in highly functionalised coumarin structures to afford new analogues of the antibiotic novobiocin. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: antibacterials; coumarin; sulfonyl compounds; palladium catalyst; organotin reagents.
Novobiocin 1 and clorobiocin 2 are coumarin-derived antibiotics which act as competitive inhibitors of the bacterial ATP binding gyrase B subunit, blocking negative supercoiling of relaxed DNA.1 These naturally produced antibacterials are extremely active against Gram-positive bacteria especially methicilin-resistant staphylococcus strains.2 However, their poor pharmacokinetic properties as well as toxicity issues3 have prevented them from pharmaceutical applications as antibiotics. Consequently, we have embarked on an extensive programme of chemical modifications4 aiming to improve the pharmacological and pharmacokinetic properties of this class of compounds.
We report here an efficient methodology for the preparation of 4-arylcoumarin analogues 4. The key step relies on an unexpected palladium-catalysed coupling reaction between p-toluenesulfonate derivatives 3 and aryltrialkylstannanes 5.5 ∗
Corresponding author. Tel: +00 33 1 49 91 55 80; fax: +00 33 1 49 91 50 87; e-mail: [email protected] (L. Schio)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. P I I: S0040-4039(99)02351-5
tetl 16279
1544
The leaving entity of choice in transition metal-catalysed coupling reactions with organometallic reagents is often the triflate group.6 However, we could not find a satisfactory methodology for preparing the corresponding trifluoromethanesulfonate analogue of 3b (R1 =CO2 Bn) because of stability issues. We, therefore, turned our attention to a more stable sulfonate group with the idea that the electron withdrawing coumarin moiety could decrease the electronic density of the C–OSO2 bond allowing palladium insertion. Preliminary coupling reactions were attempted with the coumarin-derived tosylate 6 using standard Stille conditions (see Table 1).7
Table 1 Palladium-catalysed coupling reactions between tosylate 6 and various organostannanes 5
1545
We were delighted to observe that organostannane 5a underwent the coupling reaction with an acceptable yield (60%). Furthermore, the scope of the tosylate-assisted coupling reaction was extended to functionalised aryl reagents (5b–d). In addition, the reaction took place effectively with heterocyclederived stannanes (5f, 5g) albeit occurring in low yield from the pyridine derived reactant 5e. Among the organostannanes investigated, only 5h failed to give the desired coupled compound (7h). No further studies were carried out to optimise these results. The developed methodology was applied promptly to the synthesis of 4-arylcoumarin analogues of novobiocin. The preparation of the key coumarin intermediates 9 and 15 from dihydroxycoumarin 8 is depicted in Scheme 1.
Scheme 1.
It is worthy of note that tosylation of 8 in pyridine occurred predominately at the O-4 position whereas silylation using triethylamine led exclusively to the 7-silyl ether derivative 11. Introduction of the carboxy group at the C-3 position was realised by Fries-type rearrangement of the 4-acyloxy derivative 12.4a,8 Tosylation of 13 was successful in dichloromethane in the presence of triethylamine. The 7-O t-butyldiphenylsilyl ether was then cleaved cleanly using HF/KF in a water–THF mixture9 to afford 15. The desired α-glycosides 17 and 18 were obtained by coupling L-rhamnopyranoside 164c with the coumarins 9 and 15 using Mitsunobu’s conditions (see Scheme 2).10 Tosylate derivatives 17 and 18 were then submitted to cross-coupling with organostannanes 5c and 5e in the presence of palladium catalysts. The catechol moiety was successfully introduced at the coumarin C-4 position from tosylate 18 to afford the corresponding analogue 19 of novobiocin.11 The yield obtained with Pd(Ph3 P)4 as catalyst was satisfactory considering the high level of functionalisation as well as the unprotected groups in the starting substrate structure 18. On the other hand, the coupling reaction performed with the pyridine-derived stannane 5e led to partial degradation of tosylate 17 when catalysed with Pd(Ph3 P)4 or PdCl2 (Ph3 P)2 . Finally, the pyridine containing derivative 20 was accessible in conditions generating in situ zero-valence palladium (Pd(OAc)2 /Ph3 P).12 In conclusion, we have developed a new variation to the methodology for carbon–carbon bond formation by a palladium-catalysed coupling reaction. In this respect, we have shown that the p-toluenesulfonyl group constitutes an efficient alternative to the widely used trifluoromethanesulfonyl moiety as a leaving group. Ease of preparation as well as chemical stability contribute to the attractiveness of the tosylate group over triflate. The developed methodology has been applied to the convergent synthesis of 4arylcoumarin analogues of novobiocin in the search for new antibacterial clinical candidates.
1546
Scheme 2.
Acknowledgements We are grateful to Didier Babin (Medicinal Chemistry) for assistance and to Didier Ferroud (Chemical Development) for fruitful discussions. References 1. (a) Lewis, R. J.; Singh, O. M.; Smith, C. V.; Skarzynski, T.; Maxwell, A.; Wonacott, A. J.; Wigley, D. B. EMBO J. 1996, 15, 1412–1420. (b) Ali, J. A.; Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry 1993, 32, 2717–2724. (c) Gellert, M.; O’Dea, M. H.; Itoh, T.; Tomizawa, J. I. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474–4478. 2. (a) For reviews on resistance in bacteria, see: (a) Resistance to Antibiotics, in Science 1994, 264, 360–393. (b) Smith, T. L.; Jarvis, W. R. Microbes and Infection 1999, 1, 795–805. 3. Goranov, I.; Avramova, K. Probl. Khig. 1975, 1, 165–170. 4. (a) Laurin, P.; Ferroud, D.; Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, M. Bioorg. Med. Chem. Lett. 1999, 9, 2079–2084. (b) Laurin, P.; Ferroud, D.; Schio, L.; Klich, M.; Dupuis-Hamelin, C; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett. 1999, 9, 2875–2880. (c) Ferroud, D.; Collard, J.; Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett. 1999, 9, 2881–2886. 5. To the best of our knowledge only one application of other arenesulfonates in palladium-catalysed coupling reactions has been described: Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992, 57, 6321–6323. 6. Ritter, K. Synthesis 1993, 735–762, and references cited therein. 7. (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–5486. (b) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040. (c) Following experimental observations, yields were higher when the reactions were conducted in the dark. 8. See, for example: (a) Kappe, T.; Schnell, B. J. Heterocyclic Chem. 1996, 33, 663–670. (b) Tabuchi, H.; Hamamoto, T.; Miki, S.; Tejima, T.; Ichihara, A. Tetrahedron Lett. 1993, 34, 2327–2330. (c) Eisenhauer, H. R.; Link, K. P. J. Am. Chem. Soc. 1953, 75, 2044–2045. 9. To be published elsewhere. 10. (a) For the synthesis of glycosides via the Mitsunobu reaction, see: Roush, W. R.; Lin, X. F. J. Org. Chem. 1991, 56, 5740–5742, and references cited therein. (b) The Mitsunobu reaction has been widely used in our programme for creating the glycosidic linkage between various saccharides and hydroxylaryl moieties. Usually equivalents of reagents (Ph3 P/DEAD) were necessary for reaction completion. Consequently, laborious purification steps were required to isolate the desired α-glycoside from complex crude mixtures. For example, pure 17 was obtained after several triturating manipulations in dichloromethane and ether. 11. From 17, the coupling reaction with 5c realised in the same experimental conditions occurred in 34% yield. 12. Preparation of 20: a mixture of tosylate 17 (129 mg, 0.21 mmol), organostannane 5e (93 mg, 0.25 mmol), Pd(OAc)2 (9.7 mg, 0.019 mmol) and Ph3 P (10.4 mg, 0.039 mmol) was stirred overnight in refluxing dioxane (5 ml). After concentration at
1547 reduced pressure the reaction mixture was purified by flash chromatography on silica gel (hexane:ethyl acetate: 30:70 v/v) to afford 20 (30 mg, 27% yield). TLC, SiO2 , hexane:ethyl acetate: 30:70 (v/v), Rf =0.27; IR (CHCl3 , ν cm−1 ): 3608 (OH), 3448 (C_C-NH), 1714, 1696 (C_O), 1603, 1567, 1491 (C_C). 1 H NMR (300 MHz, CDCl3 , ppm): δ 9.07 (m, NH), 8.78 (m, 1H), 7.88 (t, J=8 Hz, 1H), 7.6–7.4 (m, 3H), 7.06 (d, J=9 Hz, 1H), 6.76 (m, 1H), 6.18 (s, 1H), 5. 92 (m, 1H), 5.44 (s, 1H), 5.37 (dd, J=10 Hz, J=3 Hz, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.49 (s, 3H), 3.46 (t, J=9 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 1.26 (d, J=6 Hz, 3H). MS m/e (relative intensity): 521 (MH+ , 15), 268 (53), 254 (35), 108 (100).
Tetrahedron Letters 41 (2000) 1543–1547
Tosylates in palladium-catalysed coupling reactions. Application to the synthesis of arylcoumarin inhibitors of gyrase B Laurent Schio,∗ Fabienne Chatreaux and Michel Klich Medicinal Chemistry, Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France Received 16 November 1999; accepted 12 December 1999
Abstract The palladium-catalysed coupling reaction between tosylate derivatives and organostannanes has been investigated as a methodology for carbon–carbon bond formation. Aryl substituents have been successfully incorporated even in highly functionalised coumarin structures to afford new analogues of the antibiotic novobiocin. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: antibacterials; coumarin; sulfonyl compounds; palladium catalyst; organotin reagents.
Novobiocin 1 and clorobiocin 2 are coumarin-derived antibiotics which act as competitive inhibitors of the bacterial ATP binding gyrase B subunit, blocking negative supercoiling of relaxed DNA.1 These naturally produced antibacterials are extremely active against Gram-positive bacteria especially methicilin-resistant staphylococcus strains.2 However, their poor pharmacokinetic properties as well as toxicity issues3 have prevented them from pharmaceutical applications as antibiotics. Consequently, we have embarked on an extensive programme of chemical modifications4 aiming to improve the pharmacological and pharmacokinetic properties of this class of compounds.
We report here an efficient methodology for the preparation of 4-arylcoumarin analogues 4. The key step relies on an unexpected palladium-catalysed coupling reaction between p-toluenesulfonate derivatives 3 and aryltrialkylstannanes 5.5 ∗
Corresponding author. Tel: +00 33 1 49 91 55 80; fax: +00 33 1 49 91 50 87; e-mail: [email protected] (L. Schio)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. P I I: S0040-4039(99)02351-5
tetl 16279
1544
The leaving entity of choice in transition metal-catalysed coupling reactions with organometallic reagents is often the triflate group.6 However, we could not find a satisfactory methodology for preparing the corresponding trifluoromethanesulfonate analogue of 3b (R1 =CO2 Bn) because of stability issues. We, therefore, turned our attention to a more stable sulfonate group with the idea that the electron withdrawing coumarin moiety could decrease the electronic density of the C–OSO2 bond allowing palladium insertion. Preliminary coupling reactions were attempted with the coumarin-derived tosylate 6 using standard Stille conditions (see Table 1).7
Table 1 Palladium-catalysed coupling reactions between tosylate 6 and various organostannanes 5
1545
We were delighted to observe that organostannane 5a underwent the coupling reaction with an acceptable yield (60%). Furthermore, the scope of the tosylate-assisted coupling reaction was extended to functionalised aryl reagents (5b–d). In addition, the reaction took place effectively with heterocyclederived stannanes (5f, 5g) albeit occurring in low yield from the pyridine derived reactant 5e. Among the organostannanes investigated, only 5h failed to give the desired coupled compound (7h). No further studies were carried out to optimise these results. The developed methodology was applied promptly to the synthesis of 4-arylcoumarin analogues of novobiocin. The preparation of the key coumarin intermediates 9 and 15 from dihydroxycoumarin 8 is depicted in Scheme 1.
Scheme 1.
It is worthy of note that tosylation of 8 in pyridine occurred predominately at the O-4 position whereas silylation using triethylamine led exclusively to the 7-silyl ether derivative 11. Introduction of the carboxy group at the C-3 position was realised by Fries-type rearrangement of the 4-acyloxy derivative 12.4a,8 Tosylation of 13 was successful in dichloromethane in the presence of triethylamine. The 7-O t-butyldiphenylsilyl ether was then cleaved cleanly using HF/KF in a water–THF mixture9 to afford 15. The desired α-glycosides 17 and 18 were obtained by coupling L-rhamnopyranoside 164c with the coumarins 9 and 15 using Mitsunobu’s conditions (see Scheme 2).10 Tosylate derivatives 17 and 18 were then submitted to cross-coupling with organostannanes 5c and 5e in the presence of palladium catalysts. The catechol moiety was successfully introduced at the coumarin C-4 position from tosylate 18 to afford the corresponding analogue 19 of novobiocin.11 The yield obtained with Pd(Ph3 P)4 as catalyst was satisfactory considering the high level of functionalisation as well as the unprotected groups in the starting substrate structure 18. On the other hand, the coupling reaction performed with the pyridine-derived stannane 5e led to partial degradation of tosylate 17 when catalysed with Pd(Ph3 P)4 or PdCl2 (Ph3 P)2 . Finally, the pyridine containing derivative 20 was accessible in conditions generating in situ zero-valence palladium (Pd(OAc)2 /Ph3 P).12 In conclusion, we have developed a new variation to the methodology for carbon–carbon bond formation by a palladium-catalysed coupling reaction. In this respect, we have shown that the p-toluenesulfonyl group constitutes an efficient alternative to the widely used trifluoromethanesulfonyl moiety as a leaving group. Ease of preparation as well as chemical stability contribute to the attractiveness of the tosylate group over triflate. The developed methodology has been applied to the convergent synthesis of 4arylcoumarin analogues of novobiocin in the search for new antibacterial clinical candidates.
1546
Scheme 2.
Acknowledgements We are grateful to Didier Babin (Medicinal Chemistry) for assistance and to Didier Ferroud (Chemical Development) for fruitful discussions. References 1. (a) Lewis, R. J.; Singh, O. M.; Smith, C. V.; Skarzynski, T.; Maxwell, A.; Wonacott, A. J.; Wigley, D. B. EMBO J. 1996, 15, 1412–1420. (b) Ali, J. A.; Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry 1993, 32, 2717–2724. (c) Gellert, M.; O’Dea, M. H.; Itoh, T.; Tomizawa, J. I. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474–4478. 2. (a) For reviews on resistance in bacteria, see: (a) Resistance to Antibiotics, in Science 1994, 264, 360–393. (b) Smith, T. L.; Jarvis, W. R. Microbes and Infection 1999, 1, 795–805. 3. Goranov, I.; Avramova, K. Probl. Khig. 1975, 1, 165–170. 4. (a) Laurin, P.; Ferroud, D.; Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, M. Bioorg. Med. Chem. Lett. 1999, 9, 2079–2084. (b) Laurin, P.; Ferroud, D.; Schio, L.; Klich, M.; Dupuis-Hamelin, C; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett. 1999, 9, 2875–2880. (c) Ferroud, D.; Collard, J.; Klich, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett. 1999, 9, 2881–2886. 5. To the best of our knowledge only one application of other arenesulfonates in palladium-catalysed coupling reactions has been described: Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992, 57, 6321–6323. 6. Ritter, K. Synthesis 1993, 735–762, and references cited therein. 7. (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–5486. (b) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3040. (c) Following experimental observations, yields were higher when the reactions were conducted in the dark. 8. See, for example: (a) Kappe, T.; Schnell, B. J. Heterocyclic Chem. 1996, 33, 663–670. (b) Tabuchi, H.; Hamamoto, T.; Miki, S.; Tejima, T.; Ichihara, A. Tetrahedron Lett. 1993, 34, 2327–2330. (c) Eisenhauer, H. R.; Link, K. P. J. Am. Chem. Soc. 1953, 75, 2044–2045. 9. To be published elsewhere. 10. (a) For the synthesis of glycosides via the Mitsunobu reaction, see: Roush, W. R.; Lin, X. F. J. Org. Chem. 1991, 56, 5740–5742, and references cited therein. (b) The Mitsunobu reaction has been widely used in our programme for creating the glycosidic linkage between various saccharides and hydroxylaryl moieties. Usually equivalents of reagents (Ph3 P/DEAD) were necessary for reaction completion. Consequently, laborious purification steps were required to isolate the desired α-glycoside from complex crude mixtures. For example, pure 17 was obtained after several triturating manipulations in dichloromethane and ether. 11. From 17, the coupling reaction with 5c realised in the same experimental conditions occurred in 34% yield. 12. Preparation of 20: a mixture of tosylate 17 (129 mg, 0.21 mmol), organostannane 5e (93 mg, 0.25 mmol), Pd(OAc)2 (9.7 mg, 0.019 mmol) and Ph3 P (10.4 mg, 0.039 mmol) was stirred overnight in refluxing dioxane (5 ml). After concentration at
1547 reduced pressure the reaction mixture was purified by flash chromatography on silica gel (hexane:ethyl acetate: 30:70 v/v) to afford 20 (30 mg, 27% yield). TLC, SiO2 , hexane:ethyl acetate: 30:70 (v/v), Rf =0.27; IR (CHCl3 , ν cm−1 ): 3608 (OH), 3448 (C_C-NH), 1714, 1696 (C_O), 1603, 1567, 1491 (C_C). 1 H NMR (300 MHz, CDCl3 , ppm): δ 9.07 (m, NH), 8.78 (m, 1H), 7.88 (t, J=8 Hz, 1H), 7.6–7.4 (m, 3H), 7.06 (d, J=9 Hz, 1H), 6.76 (m, 1H), 6.18 (s, 1H), 5. 92 (m, 1H), 5.44 (s, 1H), 5.37 (dd, J=10 Hz, J=3 Hz, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.49 (s, 3H), 3.46 (t, J=9 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 1.26 (d, J=6 Hz, 3H). MS m/e (relative intensity): 521 (MH+ , 15), 268 (53), 254 (35), 108 (100).